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The main results of the ONgoing Telmisartan Alone and in Combination with Ramipril Global EndpoinT (ONTARGET) trial published in 2008 were possibly the first to demonstrate substantial issues with the combination of drugs from two different classes of renin–angiotensin system (RAS) inhibitors [1]. The ONTARGET Investigators reported that combination of the angiotensin-converting enzyme (ACE) inhibitor, ramipril, with the angiotensin receptor blocker (ARB), telmisartan, conferred no demonstrable benefit for the primary cardiovascular outcome over monotherapy with ramipril despite achieving mean blood pressures that were lower by 2.4/1.4 mmHg. On the contrary, this dual therapy did result in more frequent adverse effects including symptomatic hypotension, syncope and renal dysfunction [1,2]. A second study on the renal results [2] confirmed that the composite outcome of dialysis, doubling of serum creatinine and death, occurred more frequently with combination therapy (1233 events; 14.5%) than with ramipril alone (1150 events; 13.4%) (P < 0.04), but reported divergence in the effects on the separate elements of this outcome. Thus the increase in urinary albumin excretion was less with dual therapy than with ramipril alone, whereas dialysis or doubling of serum creatinine was more frequent [2]. These findings caused a flurry of comment and analysis, some of it supportive and positive and some more negative [3–7].

These issues were highlighted again on 20 December 2011, when Novartis announced through a press release, that the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), which combined two different inhibitors of the RAS was being stopped prematurely, on advice of the Data Safety and Monitoring Committee, because of lack of benefit, combined with higher incidence of adverse events. ALTITUDE compared the use of aliskiren, a direct renin inhibitor, with the use of placebo in patients with type 2 diabetes and cardiovascular disease, renal disease or both, who were already receiving either an ACE inhibitor or an ARB [8]. The results of the interim analysis that led to premature termination at the end of 2011, also suggested a significant excess of stroke with combination therapy. Accordingly, the ONTARGET investigators decided to revisit their trial, to examine the effects of dual therapy on the risk of stroke in more detail, as reported in this issue of the Journal [9].

The main ONTARGET trial enrolled 25 620 individuals with vascular disease or high-risk diabetes who were randomly assigned to receive 10 mg ramipril per day, 80 mg of telmisartan per day or both drugs (combination therapy) [1]. The analyses in this issue of the Journal, examine the effects of the randomized treatments in a subgroup of 9628 patients with diabetes with data available on estimated glomerular filtration rate (eGFR) and urinary albumin excretion, who participated in ONTARGET [9]. Of this subgroup, 3163 had nephropathy (micro-albuminuria and/or an eGFR below 60 ml/min per 1.73 m2) and 6465 did not. SBP decreased more during follow-up in patients on dual therapy than those on monotherapy with either ramipril or telmisartan (−7.1 vs. −5.3 mmHg; P < 0.0001).

Whereas the stroke rate was higher in the subset with nephropathy than those without (1.5 vs. 1.0 per 100 patient-years) the effects of dual therapy and monotherapy were similar in both subgroups (1.59 vs. 1.55 and 1.01 vs. 1.08 per 100 patient-years). A more detailed subdivision of the trial population into six renal subgroups according to albuminuria and eGFR did not reveal any interaction between any renal sub-group and the effects of randomized treatment on the risk of stroke or other major outcomes. However, as in the earlier reports of the main results of ONTARGET [1,2], there was once again a significant surfeit of symptomatic hypotension and hyperkalemia in those on dual therapy and a clear tendency to more frequent need for dialysis for acute renal injury [9].

One other set of analyses is of interest [9]. Upon pooling all 9628 participants, irrespective of randomized treatment allocation, it was clear that the incidence of stroke was lower in those with lower on-treatment blood pressure, even within the normotensive range. This was so whether the individuals did or did not have nephropathy. There results accord well with analyses from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial in patients with recurrent stroke [10].

A number of issues warrant discussion. The first is the results of the ALTITUDE trial in patients with type 2 diabetes. When this was stopped prematurely in December 2011, the interim analysis that led the independent Data Safety and Monitoring Committee to recommend closure suggested a higher risk of stroke with a hazard ratio of 1.34 (P < 0.044). That was the state of knowledge available to the ONTARGET investigators when they undertook the present analyses. As it happened, and as fully documented in the recently published ALTITUDE main results study [11], with the subsequent orderly study closeout and identification of 72 more patients with adjudicated stroke, the effect size for stroke was reduced and was no longer significant (hazard ratio 1.22, P = 0.11). However, the basic reasons for stopping the ALTITUDE trial were confirmed – a clear lack of any overall benefit, either cardiovascular or renal, and an excess of adverse effects including hyperkalemia and hypotension, and a tendency to an excess of renal impairment [11].

The second issue is the failure of dual therapy to reduce the risk of stroke, despite a clear advantage in lowering SBP compared to monotherapy, by around 2 mmHg more in both the main trial [1] and in these latest analyses in the diabetic subgroup [1]. Given the analyses from ONTARGET demonstrating that reduction in the risk of stroke is clearly related to the degree of blood pressure lowering achieved, both in the whole trial population [12,13] and in the present diabetic subgroup [9], this requires some further explanation. It could point to some unidentified but undesirable effects of combining two different classes of RAS inhibitors.

The third issue concerns the renal effects of combination therapy with two classes of RAS inhibitors. It seems likely that this does reduce the incidence or progression of proteinuria [1,2,5–7]. Hence, those who favour dual RAS therapy can point to the well established nexus of proteinuria, not only with progression of renal disease, but also with the risk of major cardiovascular disease including stroke and coronary heart disease. However, it is also clear from ONTARGET, that both in the whole trial population and in the diabetic subset, dual therapy causes an overall excess of renal dysfunction compared to monotherapy, with more rapid decline in eGFR, more frequent need for acute dialysis and greater risk of end stage renal disease [1,2,9]. Whereas there may be sub-populations in which the actions on the kidney are overall beneficial, such groups remain to be clearly identified.

Finally, what is the place of combination therapy with different classes of RAS inhibitors today? It seems clear from both the ONTARGET and the ALTITUDE trials that such dual therapy confers no benefit on major composite cardiovascular outcomes, nor on separate outcomes such as mortality, coronary disease or stroke. It is also clear that the combinations used in both trials, whereas different, were each associated with an excess of adverse events such as hypotension, hyperkalemia and renal impairment. Although there may be some very specific clinical situations in which the combination of two different RAS inhibitors is useful, possibly in some forms of heart failure or some sub-populations with heavy proteinuria, the onus remains on the protagonists to clearly define these clinical populations and to establish the benefits that might accrue. On the contrary, it is now clear that the combination of any two different classes of RAS inhibitors such as ACE inhibitors, ARBs or direct renin inhibitors, is not indicated for the routine treatment of patients with hypertension or with diabetes.

ACKNOWLEDGEMENTS

Conflicts of interest

J.C. has received research grants from Servier, administered through the University of Sydney, as Principal Investigator for the PROGRESS and ADVANCE trials and for the ADVANCE-ON post-trial follow-up study. He has also received honoraria and travel support from Servier for speaking about these studies at scientific meetings.